We will attemmpt to establish the nature of intrinsic metabolic defects underlying genetic diabetes in the mouse. This project will focus on the basis of secretory, biosynthetic, and morphological anomalies exhibited by the endocrine pancreas and hypothalamus. Utilizing cultured islet cells from normal and diabetes mice, as well as in vitro preparations of islets and ventrolateral hypothalamus, we shall screen for any abnormalities that may persist in vivo under chemically-defined conditions. Parameters observed to be abnormal in vitro will be evaluated in intact diabetic animals, and advantage will be taken of having the diabetes gene on several different inbred stocks to establish the nature of modifying genes that can predispose the animal to a mild or severe diabetes. We have already observed increased glucagon secretion and biosynthesis in cultures of islet cells from the diabetic strain which develops severe diabetes, and have further documented altered paracrine relationships between islet cells, as well as a qualitatively-altered hypothalamus. Our work suggests that the lesion(s) produced by the mutation is not organ-specific, but may be widely expressed in secretory tissues.